N-(4-(6,7-Disubstituted-quinolin-4-yloxy)-3-fluorophenyl)-2-oxo-3-phenylimi- dazolidine-1-carboxamides: A novel series of dual c-Met/VEGFR2 receptor tyrosine kinase inhibitors Michael Mannion a , Stéphane Raeppel a, * , Stephen Claridge a , Nancy Zhou a , Oscar Saavedra a , Ljubomir Isakovic a , Lijie Zhan a , Frédéric Gaudette a , Franck Raeppel a , Robert Déziel a , Normand Beaulieu b , Hannah Nguyen b , Ian Chute b , Carole Beaulieu b , Isabelle Dupont b , Marie-France Robert b , Sylvain Lefebvre b , Marja Dubay c , Jubrail Rahil c , James Wang d , Hélène Ste-Croix b , A. Robert Macleod b,  , Jeffrey M. Besterman b , Arkadii Vaisburg a a Department of Medicinal Chemistry, MethylGene Inc., 7220 rue Frederick-Banting, Montréal, QC, Canada H4S 2A1 b Department of Cell Biology and Pharmacology, MethylGene Inc., 7220 rue Frederick-Banting, Montréal, QC, Canada H4S 2A1 c Department of Lead Discovery, MethylGene Inc., 7220 rue Frederick-Banting, Montréal, QC, Canada H4S 2A1 d Department of PK/Analytical Chemistry, MethylGene Inc., 7220 rue Frederick-Banting, Montréal, QC, Canada H4S 2A1 article info Article history: Received 21 August 2009 Revised 6 October 2009 Accepted 8 October 2009 Available online 13 October 2009 Keywords: c-Met VEGFR2 RTK inhibitors Quinoline scaffold Oncology abstract A series of N-(4-(6,7-disubstituted-quinolin-4-yloxy)-3-fluorophenyl)-2-oxo-3-phenylimidazolidine-1- carboxamides targeting c-Met and VEGFR2 tyrosine kinases was designed and synthesized. The com- pounds were potent against these two enzymes with IC 50 values in the low nanomolar range in vitro, pos- sessed favorable pharmacokinetic profiles and showed high efficacy in vivo in several human tumor xenograft models in mice. Ó 2009 Elsevier Ltd. All rights reserved. Receptor tyrosine kinases (RTKs) play crucial roles in signal transduction pathways and cellular processes, and many are impli- cated in cancer. 1 c-Met [the receptor for hepatocyte growth factor/ scatter factor, (HGF/SF)] 2 and members of the vascular endothelial growth factor receptor (VEGFR) 3 family1 including VEGFR1 (Flt-1), VEGFR2 (KDR) and VEGFR3 (Flt-4) are among the RTKs under investigation as potential targets for the development of small molecule cancer therapeutics. c-Met activation results in numer- ous biological responses, including cell migration and invasion, proliferation and survival, morphogenesis, and angiogenesis. While c-Met is involved in normal processes during embryonic develop- ment and wound healing, its deregulation is associated with tumorigenesis and correlates with poor prognosis in cancer pa- tients. 2 c-Met has been shown to cooperate synergistically with the VEGFRs, key players in tumor angiogenesis. 3 Molecules that po- tently inhibit both c-Met 4 and VEGFR 5 may have advantage over VEGFR-selective or c-Met-selective molecules since they can target multiple pathways involved in tumor cell survival, angiogenesis and metastasis. Thus, the combined inhibition of both c-Met and VEGFR signaling represents a promising approach to cancer treatment. 6 The drug Sunitinib (Sutent TM ) 7 from Pfizer, recently approved by the FDA for the treatment of both renal cell carcinomas (RCC) and imatinib-resistant gastrointestinal stromal tumors (GIST), is an example of a multi-targeted RTK inhibitor that targets VEGFR but not c-Met. Conversely, PHA-665752 (2) 8 is a potent inhibitor of c-Met but a weak inhibitor of VEGFR2. The dual c-Met/VEGFR2 inhibitors (3) discovered by Kirin Brewery 9 in 2003 and the related compound described by Exelixis (4) 10 inspired our work in this area. We have previously reported a family of dual c-Met/VEGFR2 inhibitors in which the dimethoxyquinoline fragment of 3 was re- placed by a 2-substituted thieno[3,2-b]pyridine system, exempli- fied by 5. 11 While exploring the replacement of the acylthiourea head group of 5 by other functionalities, we discovered that 0960-894X/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved. doi:10.1016/j.bmcl.2009.10.040 * Corresponding author. Tel.: +1 514 337 3333; fax: +1 514 337 0550. E-mail address: raeppels@methylgene.com (S. Raeppel).   Present address: Isis Pharmaceuticals, 1896 Rutherford Road, Carlsbad, CA 92008, USA. Bioorganic & Medicinal Chemistry Letters 19 (2009) 6552–6556 Contents lists available at ScienceDirect Bioorganic & Medicinal Chemistry Letters journal homepage: www.elsevier.com/locate/bmcl